Cyclosporins are cyclic oligopeptides of microbiological origin. Due to its immunosuppressive effect, cyclosporin is widely used: in kidney, liver, heart, lung, pancreas, skin and cornea transplatations in order to prevent the ejection of the transplanted organ; in bone marrow transplantations, to inhibit the antibody production of the transplanted bone marrow against the host organism (graft-versus-host disease); further for healing autoimmune diseases such as rheumatoid arthritis, diabetes mellitus I, systematic lupus erythematosis, scleroderma, Wegener's granulomatosis, eosinophilic fascitis, primary liver cyrrhosis, Graves' and Crohn's diseases. Similarly, it is used for the treatment of myasthenia gravis, multiplex sclerosis and psoriasis.
Cyclosporins are practically water-insoluble substances formed from neutral amino acids of hydrophobic character. As a consequence of their high molecular weight (over 1000), poor water-solubility and weak absorption [O. Siddiqui and Y. W. Chien: Nonparenteral Administration of Peptide and Protein Drugs. CRC Crit. Rev. Ther. Drug Car. 3, 195-208 (1986)], they are absorbed only to an insignificant extent from the gastrointestinal tract when administered directly or in the traditional pharmaceutical formulations (tablets, capsules and the like).
Thus, the most important aim of developing cyclosporin-containing pharmaceutical compositions is to find a solution for this problem, by means of which the absorption and bioavailability of the active agent can successfully be improved.
A number of methods are known from the literature, by the use of which the absorption and bioavailability of cyclosporin active agents can be increased. From these, the methods worked out for preparing solutions for oral administration are briefly summarized hereinafter.
1. Dissolution of cyclosporin in sesame oil and/or in the mixture of non-ionic surfactants and/or transesterified nonionic triglycerids and/or lecithins, ethyl oleate and transesterified nonionic surfactants and/or in a neutral oil (see e.g. the Swiss patent specification No. 636,013).
2. Dissolution of cyclosporin in the mixture of a transesterified product of a native vegetable oil with a polyalkylene polyol (such as Labrafil M 1944 CS) as well as a vegetable oil and ethanol (see e.g. the Swiss patent specification No. 641,356 and the U.S. Pat. No. 4,388,307).
The above method 1 is suitable for preparing a drink solution or drink emulsion whereas method 2 is useful for the preparation of a water-dispersible oral solution. It should be noted that the commercially available oral Sandimmun.RTM. solution (Sandoz Ltd., Basel, Switzerland) is prepared according to method 2.
Compositions with relatively high active-ingredient content can be prepared by using both methods. The disadvantage of these compositions lies in that vegetable oils are used as carrier additives which, on the one hand, endow the compositions with an unpleasant oily taste and, on the other hand, these compositions become rancid during a longer storage whereby a further undesired alteration may occur in the taste and odour of the compositions. Although the degree of rancidification could be limited by antioxidants, this process cannot completely be eliminated. Thus, the oral compositions prepared according to the above methods can be commercialized with only a relatively short expiration time.